title: A randomized double-blind clinical trial of a continuous 96-hour levobupivacaine infiltration after open or laparoscopic colorectal surgery for postoperative pain management--including clinically important changes in protein binding.
abstract: BACKGROUND
  Continuous local anesthetic infiltration has been used for pain management after open colorectal surgery. However, its application to patients undergoing laparoscopic colorectal surgery has not been examined. The aim of this prospective, randomized, double-blind, placebo-controlled clinical trial was to study the use of a commercial infiltration device in patients undergoing open or laparoscopic colorectal surgery, along with plasma concentrations of levobupivacaine, its acute-phase binding protein (alpha-1 acid glycoprotein, AAG), and the stress marker, cortisol.
  
  
  METHODS
  Eligible patients were randomized (2:1) to receive a continuous infiltration of either levobupivacaine or placebo using a commercial device (ON-Q PainBuster) inserted in the preperitoneal layer at the end of surgery. Blood was sampled for determination of levobupivacaine and AAG and cortisol concentrations. Other outcomes measured were pain scores, morbidity and mortality, time to bowel movement, mobilization, and length of hospitalization.
  
  
  RESULTS
  In patients having open surgery, the levobupivacaine treatment showed a trend toward reduced total opioid consumption. No patients reported adverse effects attributable to levobupivacaine, despite 11 patients having concentrations at some time(s) during the 96-hour infiltration of up to 5.5 mg/L exceeding a putative toxicity threshold of 2.7 mg/L. AAG concentrations measured postsurgery increased by a mean of 55% (P < 0.001) at 48 hours. Cortisol concentrations also increased significantly by a mean of 191% at 1 hour.
  
  
  CONCLUSIONS
  Continuous local anesthetic infiltration may be more beneficial in open surgery. The threshold for adverse effects from highly bound local anesthetic drugs established in healthy volunteers is of limited usefulness in clinical scenarios in which AAG concentration increases in response to surgical stress. Hence, there is scope to adopt higher doses to enhance therapeutic benefit.
authors.affiliation: *Department of Clinical Pharmacology, The Queen Elizabeth Hospital; †Discipline of Surgery; ‡Discipline of Pharmacology, University of Adelaide; §Department of Colorectal Surgery, The Queen Elizabeth Hospital; ¶Statistical Support Service, Faculty of Health Sciences, University of Adelaide; and ‖Acute Pain Service, Department of Anaesthesia, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Sumithra
authors.initials: S
authors.lastname: Krishnan
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Morris
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hewett
authors.forename: John
authors.initials: J
authors.lastname: Field
authors.forename: Alex
authors.initials: A
authors.lastname: Karatassas
authors.forename: Samson
authors.initials: S
authors.lastname: Tou
authors.forename: Ian S
authors.initials: IS
authors.lastname: Westley
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Wicks
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tonkin
mesh_terms: D000368:Aged; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002045:Bupivacaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003107:Colorectal Surgery; D004311:Double-Blind Method; D006760:Hospitalization; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D010535:Laparoscopy; D000077554:Levobupivacaine; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism; D059408:Pain Management / Q000379:methods; D010149:Postoperative Pain / Q000188:drug therapy*; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects*
chemical_list: D000779:Anesthetics, Local; D009961:Orosomucoid; D000077554:Levobupivacaine; D006854:Hydrocortisone; D002045:Bupivacaine